Our long term goal is to develop better ways to treat cancer by identifying, and then exploiting, tumor-specific therapeutic vulnerabilities. Our immediate aim is to improve our understanding of the fundamental biology of adult acute myelogenous leukemia (AML) and glioblastoma multiforme (GBM) and our ability to treat both of these therapeutically challenging, lethal human malignancies. Hypothesis: The central organizing hypothesis of this Program, seen as 'highly innovative' in the previous review, is that the mechanisms driving genetic and epigenetic heterogeneity identify-and may serve as targets for-new and highly effective cancer therapies. A corollary is that better understanding these mechanisms will enable more effective targeting of tumor-specific defects with the potential to improve the therapy and treated outcomes for patients with AML or GBM. Structure: The proposed research consists of 3 Projects and 3 Cores designed to build on the expertise and collaborative history of Program members (four of whom have been Project or Core leaders during the preceding funding period), together with newly added expertise in AML and GBM clinical and basic science (Core A) and in cancer bioinformatics (Core B). These new components will provide clinical expertise, well-characterized patient samples, AML and GBM disease models, and the expertise needed to take full advantage the growing role of cancer genetics, genomics and bioinformatics and fully enable and pursue Program research aims. Overall Approach: Our immediate aim is to improve knowledge of the biology of AML and GBM, and then to use this knowledge in relevant pre-clinical models to develop and validate better therapies for both tumors. Each of our Overall Program Aims reflects research developed to address the following questions: * Disease understanding: How best to integrate and use existing and newly generated data on molecular, mechanistic and functional aspects of AML and GBM to identify key aspects of tumor biology and genomics that affect response; * Therapeutic development: How to identify and test potential therapeutic vulnerabilities and exploit these to improve therapeutic effectiveness and suppress resistance mechanisms; and * Translational support: What additional information, tools and decision-making support will be needed to improve therapeutic decision-making and the treatment of individual AML or GBM patients. Impact: A better understanding of the biology of AML and GBM in relation to clinical presentation and treatment will provide the best opportunity to develop new treatment regimens that exploit tumor-specific therapeutic vulnerabilities.